HCV and HEV recurrence after liver transplantation: one antiviral therapy for two viruses

Abstract

Dear Editors, In liver transplantation (LT) recipients, the prevalence of Hepatitis E Virus (HEV)-RNA is about 1-3%, possibly leading to cirrhosis within 1-2 years [1]. Seroprevalence, without viremic infection, is highly variable, reported up to 42% in US patients treated for Hepatitis C Virus (HCV) recurrence after LT [2].We report for the first time the concomitant recurrence of HCV and HEV after LT.A 56-year-old man underwent LT for HCV, genotype (G) 1a, treatment-na€ ıve cirrhosis. He was retransplanted 6 months later for chronic rejection. Immunosuppression combined tacrolimus, mycophenolate mofetil and steroids. Two months after re-LT, transaminases raised (ALT 1493 IU/l). Tacrolimus trough level was between 6 and 8 ng/ml. HCV viral load was 6.84 log 10 IU/ml, and HCV recurrence was histologically proved. A systematic HEV-RNA screening detected an HEV G3e infection with a viral load of 5.82 log 10 IU/ml. IgM and IgG were negative. Retrospectively HEV-RNA was detectable from 3 months after the first LT. Both blood products and liver tissue of the first donor were negative. A food-borne contamination was likely. Antiviral therapy combining sofosbuvir (SOF) (400 mg/day), daclatasvir (DCV) (60 mg/day) and ribavirin (RBV) (1000 mg/day) was initiated for 24 weeks. This combination was the only available. At baseline, biology showed: Hb 13.6 g/dl, creatinine 150 lmol/l, ALT 437 IU/l. Anaemia rapidly occurred, requiring RBV dose reduction, blood transfusions and erythropoietin administration. RBV serum concentration at week (W) 12 was 4633 ng/ml with therapeutic limit of 2200 ng/ ml. RBV was further decreased to 200 ng/day. Regarding HCV, the viral load was undetectable from W6 and the patient achieved a sustained virological response after W12 of treatment discontinuation (SVR12). HEV PCR had flare-up at W8 (Fig. 1), but was undetectable from W12. The G1634R mutation in the RNA-dependent RNA polymerase region of HEV was detected in the baseline serum. In this context, RBV was maintained for 8 W after SOF/DCV discontinuation. No resistance tests were performed for HCV.First, the extensive investigation we performed retrospectively, looking for the route of HEV transmission, leads to diagnosis of viral recurrence rather than primo infection.Second, HCV and HEV can simultaneously recur after LT as demonstrated by our work-up. The HEV diagnosis cannot be made on liver biopsy, due to the prevalence of HCV histological features; thus, HEV needs to be systematically tested in case of increase in transaminases. Moreover, since serology is not sensitive enough [1], HEV PCR should be always tested.Third, a three-month course of RBV remains the recommended treatment for chronic HEV infection, with a SVR of 78% [3]. Dao Thi et al. [4] showed that SOF inhibited HEV-RNA replication in vitro and had an additive effect with RBV, but these findings need to be clinically validated. Therefore, the choice of HCV antiviral therapy for a patient with concomitant HEV infection should be RBV based.The HEV flare prompted us to seek HEV-R...

Antiviral Candidates for Treating Hepatitis E Virus Infection

“…Clinically, sofosbuvir has been used in a few individual cases with or without ribavirin to treat HEV G3-infected patients with variable success (63,(65)(66)(67)(68), ranging from a reduction of HEV RNA to undetectable levels (63,66) to treatment failure or relapse following treatment (65,67,68). These mixed reports of efficacy have raised questions around the pursuit of sofosbuvir as an HEV antiviral (69), indicating that further work is required to ascertain its suitability as an anti-HEV therapeutic.…”

Treatment for chronic hepatitis E virus infection: A systematic review and meta‐analysis

“…Sofosbuvir has been proposed as an alternative treatment method for chronic hepatitis E. Although it seems to have some efficacy in vitro, 78 only two out of seven patients described in case reports achieved a SVR 79‐86 . Combination of peg‐IFN and RBV has been described in three patients, resulting in SVR in one patient 87‐89 .…”

Sofosbuvir Add-on to Ribavirin Treatment for Chronic Hepatitis E Virus Infection in Solid Organ Transplant Recipients Does Not Result in Sustained Virological Response

“…Although the antiviral effect of sofosbuvir in vitro was promising, it seems that in patients with chronic HEV infection who failed on ribavirin monotherapy and for whom reduction of immunosuppressive medication or treatment with PEG-IFN is not an option, the above-mentioned addition of sofosbuvir to ribavirin treatment may not be the salvage therapy we hoped for, in spite of the 2 case reports with successful combination treatment [8, 12]. The liver transplant recipient with clearance of HEV under sofosbuvir plus ribavirin treatment had a concurrent HCV infection [8]. In theory, the treatment of HCV may have triggered an immunological response that induced HEV clearance as well.…”

“…Two liver transplant recipients with a HCV and HEV coinfection were treated with sofosbuvir and daclatasvir. In 1 patient, this therapy regimen was not effective in clearing the chronic HEV infection, whereas in the other patient both HCV and HEV were cleared after 12 weeks of treatment; this latter patient was also treated with ribavirin [7, 8]. Four additional cases of ribavirin plus sofosbuvir therapy for chronic HEV infections have been described.…”